Nitroreduction is not involved in the genotoxicity of 2-nitropropane in cultured mammalian cells

Abstract

We have investigated the importance of nitroreduction for the genotoxicity of the carcinogen 2-nitropropane (2-NP) in primary cultures of rat hepatocytes and in V79 Chinese hamster cells. Induction of DNA repair synthesis was used as an indicator of genotoxic effects in hepatocytes. Genotoxicity in V79 cells was determined as induction of DNA repair, micronuclei and mutations to 6-thioguanine (TG) resistance. Both hepatocytes and V79 cells were found capable of reducing and oxidizing 2-NP. Reduction of 2-NP was indicated by the formation of acetone oxime, the tautomeric form of 2-nitrosopropane, the first reduction product of 2-NP. Oxidation of 2-NP was indicated by the production of acetone and nitrite. 2-NP strongly elicited repair in hepatocytes, but acetone oxime and the products of a possible further nitroreduction, isopropyl hydroxylamine (IPHA) and 2-aminopropane did not. None of the reduction products caused repair synthesis in V79 cells. However, in these cells IPHA and 2-NP increased the frequency of TG-resistant mutants. IPHA also markedly induced micronuclei. This was not seen with 2-NP. Acetone oxime was not genotoxic in V79 cells. The observations suggest that reduced metabolites are responsible neither for the induction of DNA repair synthesis by 2-NP in hepatocytes nor for the induction of gene mutations by 2-NP in V79 cells.